The Genetics of Hypertension Associated Treatments (GenHAT) is proposed as a prospective study to examine whether the association between selected hypertensive genes and combined fatal coronary heart disease and nonfatal myocardial infarction in high-risk hypertensives is modified by the type of antihypertensive treatment, leading to differential risks of coronary heart disease (CHD). Such gene-treatment interactions might shed important light On the variation in patient response to antihypertensive agents, and improve our ability to pick the right antihypertensive for specific patients. GenHAT will be an ancillary study to ALLHAT (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial). ALLHAT recruited 42,515 hypertensives and randomized them to one of four antihypertensive agents (lisinopril, chlorthalidone, amlodipine, and doxazosin); follow-up will be completed in March, 2002. GenHAT will characterize hypertension genetic variants and determine their interaction with antihypertensive treatments in relation to CHD. DNA from frozen clots stored at the ALLHAT Central Laboratory will be used to genotype variants of hypertension genes (angiotensinogen -6, angiotensin converting enzyme insertion/deletion, angiotensin type- 1 receptor, alpha-adducin, beta2 adrenergic receptor, lipoprotein lipase, and 10 new hypertension variants expected to be discovered during the course of the study). In addition to the primary aim, a number of secondary aims will be undertaken to evaluate gene- treatment interactions in relation to other endpoints, including all-cause mortality, stroke, heart failure, left ventricular hypertrophy, decreased renal function, peripheral arterial disease, and blood pressure lowering. Because of the ethnic and gender diversity of ALLHAT, we will also assess effects of these variants on outcomes in key subgroups (age >65 years, women, African Americans, Type II diabetics), and whether the gene-treatment interactions in relation to outcomes are consistent across subgroups. This proposal has the advantages of (1) incorporation into an already funded clinical trial, and (2) collaboration with experienced investigators in genetic analysis (Drs. Boerwinkle and Eckfeldt) and clinical trials (Drs. Davis and Ford). It will, therefore, provide an important and cost-efficient contribution to the knowledge and understanding of the treatment of hypertension.